Formulation and manufacture of pharmaceuticals by impregnation onto porous carriers

ABSTRACT

The present invention provides methods for impregnating a porous carrier with an active pharmaceutical ingredient (“AP”), the methods comprising steps: a) dissolving at least one API in a solvent to form an API solution; b) contacting a porous carrier with the at least one API of step (a) in a contactor to form an API impregnated porous carrier; and c) drying the at least one API impregnated porous carrier.

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of priority to U.S. ProvisionalApplication No. 61/376,568 (filed Aug. 24, 2010) entitled “FORMULATIONAND MANUFACTURE OF PHARMACEUTICALS BY IMPREGNATION ONTO POROUSCARRIERS,” the entire contents of which are incorporated herein byreference.

FIELD OF THE INVENTION

The described invention relates to drug product development andmanufacturing thereof.

BACKGROUND

Approximately 65% of all prescription drugs are manufactured as soliddosage forms, which include tablets and capsules. In both cases thefinal formulation consists of a carrier (or mixtures of carriers) and anactive pharmaceutical ingredient (“API”) which is homogeneouslydistributed throughout the carrier. For very potent drugs the amount ofAPI in the solid dosage form can be as low as 0.1% by weight. This verylow API loading poses one of the biggest problems in pharmaceuticalproduct development: the control of blend uniformity. Low API contentvariability in the blend or high blend homogeneity are highly desiredand strictly enforced by the U.S. Food and Drug Administration (“FDA”).Current guidelines developed by the FDA require API content variabilityin finished drug products to have relative standard deviation (“RSD”) ofno higher than 6%, with lower being better. In the commonly availableapproaches for blend uniformity control (for example, direct blending,wet or dry granulation) as the API concentration decreases, thevariability of the blend increases; this makes it very difficult to meetFDA's requirements for low drug loadings. Therefore a process or methodthat is able to tightly control API variability in blends, regardless ofdrug loadings, has become very desirable.

Another important aspect of pharmaceutical process development is thefinal cost. As pharmaceutical companies strive to develop cheaper andmore affordable drugs, any possible elimination of lengthy and expensiveunit operations will become commercially advantageous. One group of suchunit operations is associated with the control of API attributes (size,size distribution, shape, crystal form, bulk density, etc.). These unitoperations can include crystallization and various milling andde-lumping steps. The need for control of API attributes is solelydictated by the drug product development and usually is associated withimprovements in blend uniformity, drug release profile, and physicalstability of the finished product. Having a formulation process that canmake these and other steps unnecessary will provide a large advantage topharmaceutical companies and the industry as a whole.

In addition to cost savings in the manufacturing process, a veryimportant part in the overall economics is the cost associated withresearch and development efforts. Currently, to at least some degree,these research investments are driven by the difficulty of theparticular drug formulation. This generally is true for new molecules,where processing difficulties can cause delays in launching the product,and for generic products, where difficulties in developing a suitableformulation often are the paramount factor controlling successfuldevelopment. These difficulties can be associated with the APIproperties (difficult to control crystal form, low bulk density,cohesive powders, difficult to achieve particle size distribution(“PSD”), etc.) or with the drug product properties (low blenduniformity, inconsistent release profile, poor powder flow, etc.). Thereis interest in having a robust manufacturing process that can be appliedto a number of products regardless of the individual API properties andspecifics. One area that can greatly benefit from such a robustmanufacturing platform is the preparation of clinical supplies, whetherfor early phase studies for new molecules, or for bioequivalence studiesfor generic versions of existing products. The uncertainty of the drug'sfuture at that stage makes such a platform extremely cost effective andhighly desirable for pharmaceutical companies.

The described invention addresses these problems. The describedinvention provides a method for impregnating a drug solution throughoutthe volume of a porous carrier by spraying the solution onto the carrierin a fluid bed processor, generating a composite particle in which APIbulk properties are no longer important.

SUMMARY

According to one aspect, the described invention provides a method fordistributing at least one active pharmaceutical ingredient (API) acrossa volume of a preformed porous carrier via impregnation, the methodcomprising: (a) dissolving at least one active pharmaceutical ingredient(API) in a solvent to form an active pharmaceutical ingredient (API)solution; (b) contacting a porous carrier with the at least one activepharmaceutical ingredient (API) of (a) in a contactor to form an activepharmaceutical ingredient (API) impregnated porous carrier; and (c)drying the at least one active pharmaceutical ingredient (API)impregnated porous carrier.

According to one embodiment of the method, the method provides canachieve a substantially uniform distribution of one or more APIs acrossthe volume of a preformed porous support such that any single APIcontent variability in a finished drug product has a relative standarddeviation of less than 3%. According to another embodiment, thecontacting step (b) and drying step (c) takes place in a fluidized bed.According to another embodiment, the active pharmaceutical ingredient(API) impregnated porous carrier is dried in a contactor during step(b). According to another embodiment, the contactor comprises anagitated vessel, a tumbler, and a tray oven. According to anotherembodiment, contacting step (b) comprises spraying. According to anotherembodiment, the at least one pharmaceutical ingredient comprisesacetaminophen, ibuprofen, indometacin/indomethacin, flufenamic acid,Imatinib, flufenamic acid, erlotinib hydrochloride, vitamin D, asteroid, estrodial, or a combination thereof. According to anotherembodiment, the preformed porous carrier is of a high porosity of 20% to80% pores by volume. According to another embodiment, the porous carrieris a pharmaceutical carrier. According to another embodiment, the porouscarrier is CaHPO₄. According to another embodiment, the porous carrieris anhydrous CaHPO₄. According to another embodiment, the activepharmaceutical ingredient (API) impregnated porous carrier is a blend.According to another embodiment, the porous carrier is impregnated in acontactor comprising a fluidized bed, a stirred vessel, and a tumbler.According to another embodiment, the method further comprises preparinga final dosage form for making a substantially uniform pharmaceuticalproduct containing the at least one active pharmaceutical ingredient(API) impregnated porous carrier, wherein the final dosage form isselected from the group consisting of a tablet, a powder, a capsule, ablister pack, an inhaler, and a vial. According to another embodiment,the final dosage form is a substantially uniform pharmaceutical tabletcontaining the at least one active pharmaceutical ingredient (API)impregnated porous carrier. According to another embodiment, the finaldosage form is a substantially uniform pharmaceutical powder containingthe at least one active pharmaceutical ingredient (API) impregnatedporous carrier. According to another embodiment, the final dosage formis a capsule containing the at least one active pharmaceuticalingredient (API) impregnated porous carrier. According to anotherembodiment, the final dosage form is a blister pack containing the atleast one active pharmaceutical ingredient (API) impregnated porouscarrier. According to another embodiment, the final dosage form is aninhaler containing the at least one active pharmaceutical ingredient(API) impregnated porous carrier. According to another embodiment, thefinal dosage form is a vial containing a substantially uniform powderblend containing the at least one active pharmaceutical ingredient (API)impregnated porous carrier. According to another embodiment, the methodfurther comprises milling and further processing the at least one activepharmaceutical ingredient (API) impregnated porous carrier. According toanother embodiment, the method further comprises lubricating and furtherprocessing the at least one active pharmaceutical ingredient (API)impregnated porous carrier. According to another embodiment, the methodfurther comprises preparing a final dosage form, wherein the finaldosage form is selected from the group consisting of a tablet, a powder,a capsule, a blister pack, an inhaler, and a vial, and wherein the finaldosage form produced has enhanced bioavailability. According to anotherembodiment, the final dosage form is a substantially uniformpharmaceutical tablet containing the at least one active pharmaceuticalingredient (API) impregnated porous carrier. According to anotherembodiment, the final dosage form is a substantially uniformpharmaceutical powder containing the at least one active pharmaceuticalingredient (API) impregnated porous carrier. According to anotherembodiment, the final dosage form is a capsule containing the at leastone active pharmaceutical ingredient (API) impregnated porous carrier.According to another embodiment, the final dosage form is a blister packcontaining the at least one active pharmaceutical ingredient (API)impregnated porous carrier. According to another embodiment, the finaldosage form is an inhaler containing the at least one activepharmaceutical ingredient (API) impregnated porous carrier. According toanother embodiment, the final dosage form is a vial containing asubstantially uniform powder blend containing the at least one activepharmaceutical ingredient (API) impregnated porous carrier.

According to another aspect, the described invention provides an activepharmaceutical ingredient (API)-impregnated porous carrier, wherein atleast one active pharmaceutical ingredient (API) is impregnatedthroughout an internal surface of a porous carrier.

According to one embodiment, the at least one active pharmaceuticalingredient (API) comprises acetaminophen, ibuprofen,indometacin/indomethacin, flufenamic acid, Imatinib, flufenamic acid,erlotinib hydrochloride, vitamin D, a steroid, estrodial, or acombination thereof. According to another embodiment, the porous carrieris of a high porosity of 20% to 80% pores by volume. According toanother embodiment, the porous carrier has a high specific surface area.According to another embodiment, the porous carrier is a pharmaceuticalcarrier. According to another embodiment, the porous carrier is CaHPO₄.According to another embodiment, the porous carrier is anhydrous CaHPO₄.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows an illustrative fluidized bed impregnation system.

FIG. 2A shows photomicrographs of CaHPO₄-Emcompress®, a preformed porouscarrier. FIG. 2B shows photomicrographs of CaHPO₄ impregnated withacetaminophen (APAP).

FIG. 3A shows comparison of XRD patterns for impregnated CaHPO₄ (11.69%loading), pure CaHPO₄, and pure acetaminophen (APAP). FIG. 3B whichshows comparison of XRD patterns for various sieved fractions ofimpregnated CaHPO₄ (8.87% average loading).

FIG. 4A shows a graph of DSC analysis of sieved impregnated fractions.

FIG. 4B shows the DSC profile for pure amorphous acetaminophen (APAP)(Sheng Q., Avale, P., Saklarvala, R., Craig, D., (2008). AnInvestigation into the effects of thermal history on the crystallizationbehavior of amorphous paracetamol, European Journal of Pharmaceutics andBiopharmaceutics, 69, 364-371).

FIG. 5 shows graphs of weight fraction (%) and acetaminophen (APAP)loading (%) versus particle size fractions (μm) for impregnated CaHPO₄(average loadings 8.87% and 0.99%) and pure CaHPO₄.

FIG. 6 shows graphs of cumulative pore size distributions (pore volumevs. pore size) and tables of total surface area (m²/g) and total porevolume (cm³/g) for various sieved fractions of pure and impregnatedCaHPO₄ (high loading).

FIG. 7 shows graphs of cumulative pore size distributions (pore volumevs. pore size) and tables of total surface area (m²/g) and total porevolume (cm³/g) for various sieved fractions of pure and impregnatedCaHPO₄ (low loading).

FIG. 8A shows a dissolution profile of impregnated CaHPO₄ withacetaminophen (APAP) to a loading level of 1%. FIG. 8B shows adissolution profile of impregnated CaHPO₄ with acetaminophen (APAP) to aloading level of 8.8%. The experiments were done using baskets insteadof paddles, which are more appropriate and accurate when testingdissolution profiles of capsules. The percentage of acetaminophen (APAP)dissolved showing over 100% in FIG. 8B can be attributed to thefollowing: (1) small errors in the calibration curve used; (2) smallerror in weighing of the capsules; or (3) some moisture content in theblend due to uncontrolled storage conditions.

FIG. 9A shows a plot of particle size distributions for pure CaHPO₄,impregnated CaHPO₄ (high and low loadings) and milled impregnated CaHPO₄(high and low loadings). FIG. 9B shows numerical data of particle sizedistributions for pure CaHPO₄, impregnated CaHPO₄ (high and lowloadings) and milled impregnated CaHPO₄ (high and low loadings).

FIG. 10 (right panel) shows a graph of tablet thickness (mm) versuscompression force (kN); FIG. 10 shows (left panel) a graph of tablethardness (N) versus compression force (kN).

FIG. 11 shows a graph of shear cell measurements (normal stress, kPaversus shear stress, kPa, for pure and impregnated CaHPO₄ (high and lowloadings).

FIG. 12 shows a graph of impedance measurements (frequency, Hz, versusimpedance, M-Ohms, for pure CaHPO₄, impregnated CaHPO₄ (high and lowloadings) and milled impregnated CaHPO₄ (high and low loadings).

FIG. 13 shows an illustrative representation of the effect of milling onthe blend uniformity.

FIG. 14 shows blend uniformity results for impregnation experimentsusing a second model drug (Ibuprofen). The results indicate that themanufacturing method of the invention is not limited to onlyacetaminophen (APAP) but can be used for any other drug.

FIG. 15 shows DSC scans of various size fractions of impregnated CaHPO₄with Ibuprofen. The plots show an absence of amorphous content (upwardpeaks). They also show broadening of the melting peaks of Ibuprofen andshifting to lower melting points (pure Ibuprofen melts at 77.3° C.).

FIG. 16 shows a dissolution profile of gelatin capsules filled withCaHPO₄ impregnated with Ibuprofen at 10% loading.

DETAILED DESCRIPTION OF THE INVENTION

The described invention provides a method for impregnating a drugsolution throughout the volume of a porous carrier by spraying thesolution onto the carrier in a fluid bed processor, an agitated vessel,or a tumbling vessel, or other suitable means for ensuring uniformcontact between the porous carrier and the solution. The liquid mediumused to create said solution, hereafter referred to as the “solvent,” ischosen to have high vapor pressure and low surface tension on porouscarrier surfaces. Upon contact, capillary forces drive the solution intothe porous carrier. The solvent is concurrently or subsequentlyevaporated in a fluid bed, in an agitated vessel, in a tumbler, in atray oven, or any other device that provides uniform contact between theimpregnated material and a drying source, such as, but not limited to,dry air, providing a substantially uniform composite particle of thecarrier and the drug(s). Since the drug is deposited on the internalsurface of the carrier, the external surface properties of the carrierremain largely unchanged regardless of the concentration of drug, oreven the type of drug deposited. The dried carrier can be subsequentlymilled to further improve uniformity, and then filled into capsules,vials, aerosol blisters, or compressed into tablets.

A method known as “incipient wetness impregnation” uses capillary forcesto impregnate porous carriers in an extremely uniform manner; here,solutions are impregnated onto porous carriers as a convenient methodfor distributing small amounts of precious metals onto porous carriers.The method is usually implemented in, for example, but not limited to,large tumbler mixers equipped with spray nozzles and jacketed to allowheat exchange.

A fluidized bed (FIG. 1) provides a very high degree of mixing for thecarrier to be impregnated. As the API solution is sprayed into thefluidized bed, the spray nozzle produces very tiny droplets, a fewmicrons in diameter. These droplets containing API collide withindividual carrier particles in the so called “spray zone” and thesewetted particles are then carried away. As they move throughout thefluidized bed they begin to dry. If the temperature of the fluidizationgas is high enough, these droplets will dry immediately after collision,resulting in carrier particles coated with API. If, however, the dryingtemperature is chosen carefully (not very high), the droplets will haveenough time to penetrate the carrier particles due to capillary forces.The solvent is subsequently evaporated leaving the API inside the porouscarrier. The process is repeated as these particles re-enter the sprayzone. Therefore this process can be viewed also as a multistageimpregnation. Due to the very good mixing inside the fluidized bed andthe small droplets continuously impregnating all individual porousparticles, this process yields very high uniformity in the APIdistribution within the carrier. An important scale-up parameter thathas a significant impact on the API distribution is the spray rate,defined as:

Spray Rate=((m(API sprayed))/(Spray Time*m(carrier)))

The smaller the spray rate, the higher the API uniformity, where m(APIsprayed) is the mass of API sprayed and m(carrier) is the mass of thecarrier. In general for a given mass of API and carrier to beimpregnated, the longer the time for spraying is (or lower initial APIconcentration in the solvent) the higher the API uniformity within theblend will be. This parameter provides for a high blend uniformity forvery low drug loadings, and makes blend uniformity virtually independentof the drug loading.

The impregnation process also can be performed in additional forms,including, but not limited to, the use of agitated vessels and tumblers.The drying process also can be performed in additional forms, including,but not limited to, the use of agitated vessels, tumblers, and trayovens, or combinations thereof.

The independence of the blend uniformity from the drug loading holdstrue if the porosity of the porous carrier is independent of particlesize, and is further promoted if the particles have uniform size. Inthat case all particles moving in the fluidized bed spend largely thesame time in the spray zone receiving the same amount of drug perparticle. In practice, however, there is always some particle size andporosity distribution associated with the carrier. The flow pattern willbe different for different size groups resulting in uneven drug uptakeduring impregnation. Even if all particles receive the same amount ofAPI, the drug loading per unit mass will be different for each sizegroup due to time delays incurred in impregnating the larger particles,the possibility of saturating smaller particles, and then coating theirexternal surface. As a result, in some cases, small particles will endup with higher percent loading compared to large particles. Thisvariation combined with the fact that there will be some segregationbetween particles due to their size differences, will result in a smalldegree of API content variability in the blend. Milling the finalimpregnated material significantly reduces this variability. Breakinglarge particles results in smaller ones, some of which will have drug inthem and some of which will have less. This in turn will cause the APIvariability to be decreased in two ways. First, it will minimizesegregation since the size difference is now less pronounced. Second,small particles that have less drug in them (as a result of milling)generally will not be a problem, since they will be uniformlydistributed within the blend and their segregation will be minimizedbased on the above rationale. On the other hand, excessively intensemilling will reduce the flowability of the final powder. Therefore abalance between milling intensity and improved API variability isneeded. Gentle milling can reduce variability by half (or more in somecases) without affecting the flow properties of the impregnatedmaterial.

1. Method for Impregnating a Porous Carrier with an ActivePharmaceutical Ingredient

According to one aspect, the described invention provides a method forimpregnating a porous carrier with an active pharmaceutical ingredient(“API”), the method comprising steps:

a) dissolving at least one API in a solvent to form a API solution;

b) contacting a porous carrier with the at least one API of step (a) ina contactor to form an API impregnated porous carrier;

c) drying the API impregnated porous carrier; and

d) optionally milling the API impregnated porous carrier of (c).

Solvent

According to one embodiment, the solvent is a solvent appropriate forthe API. According to one embodiment, the solvent is of a low boilingpoint. According to another embodiment, the solvent is a green solvent.

According to another embodiment, the API solution is of a desiredconcentration. According to some such embodiments, the desiredconcentration is of a therapeutically effective amount.

According to another embodiment, the solvent provides good wetability

According to another embodiment, the solvent is not detrimental to theAPI.

According to another embodiment, the solvent has at least one of thefollowing properties: ability to dissolve the API in appropriateconcentrations, low surface tension on carrier surfaces, high vaporpressure, low toxicity, and low or null explosivity, or combinationsthereof.

Porous Carrier

According to another embodiment, the porous carrier is of a highporosity. According to some such embodiments, the porous carrier has ahigh specific surface area.

According to another embodiment, step (d) provides good flowability.According to another embodiment, step (d) provides tight particle sizedistribution (PSD) of the carrier.

According to some embodiments, the carrier is a pharmaceutical carrier.According to some embodiments, the carrier is CaHPO₄. According to someembodiments, the pharmaceutical carrier is anhydrous CaHPO₄-Emcompress®.

Contacting the API Solution

According to another embodiment, contacting step (b) comprises spraying.According to another embodiment, the spray rate is adjustable. Accordingto another embodiment, the spray rate is a controlled spray rate.According to another embodiment, the spray rate allows for scale-up.

According to another embodiment, spraying is stopped when the desiredAPI content has been achieved.

According to some embodiments, the API impregnated porous carrier can beblended with a different API or an excipient. According to oneembodiment, the blend comprises at least one API and at least one APIimpregnated porous carrier. According to one embodiment, the blendcomprises at least one API impregnated porous carrier and one excipientto facilitate downstream processing.

According to another embodiment, the blend comprising the API and porouscarrier is dried. According to some such embodiments, the blend is drieduntil a desired residual solvent content has been reached.

According to another embodiment, the atomization pressure is acontrolled atomization pressure. According to some such embodiments, theatomization pressure is an adjustable atomization pressure.

According to another embodiment, the contacting temperature is of atemperature appropriate for the solvent.

According to some embodiments, the contactor is a fluidized bed.According to some embodiments, the contactor is an agitated vessel.According to some embodiments, the contactor is a tumbler. According tosome embodiments, the contactor is a stirred vessel. According to someembodiments, the contactor is a tray oven.

According to another embodiment, the API solution is sprayed onto thecarrier in a contactor. According to another embodiment, the APIsolution is sprayed onto the porous carrier in a contactor, wherein thecontactor is an agitated vessel. According to another embodiment, theAPI solution is sprayed onto the carrier in a contactor, wherein thecontactor is a tumbler.

Drying the API Impregnated Porous Carrier

According to another embodiment, the API impregnated porous carrier isdried in a contactor. According to some embodiments, the API impregnatedporous carrier is dried in the contactor of step (b). According toanother embodiment, the API impregnated porous carrier is dried in acontactor, wherein the contactor is an agitated vessel. According toanother embodiment, the API impregnated porous carrier is dried in acontactor, wherein the contactor is a tumbler. According to anotherembodiment, the API impregnated porous carrier is dried in a contactor,wherein the contactor is a tray oven.

According to another embodiment, the API impregnated porous carrier isdried in parallel with contacting step (b). According to anotherembodiment, the API impregnated porous carrier is dried after contactingstep (b).

Milling

According to another embodiment, the API impregnated porous carrier(“impregnated carrier”) is milled to improve blend uniformity.

According to another embodiment, the milling is gentle milling.

According to another embodiment, the impregnated carrier comprises fromabout 10% API w/w/ to about 0.1% API w/w.

2. API Impregnated Fluidized Porous Carrier

According to another aspect, the described invention provides anAPI-impregnated porous carrier comprising an API impregnated porouscarrier fabricated by a method comprising steps:

a) dissolving at least one API in a solvent to form a API solution;

b) contacting a porous carrier with the at least one API of step (a) ina contactor to form an API impregnated porous carrier;

c) drying the API impregnated porous carrier; and

d) optionally milling the API impregnated porous carrier of (c).

Solvent

According to one embodiment, the solvent is a solvent appropriate forthe API. According to one embodiment, the solvent is of a low boilingpoint. According to another embodiment, the solvent is a green solvent.According to another embodiment the solvent is an inorganic or organicsolvent including, but not limited to, ethanol, methanol, isopropylalcohol (IPA), acetone, 1-propanol, 1-pentanol, acetonitrile, butanol,methyl ethyl ketone (MEK), methyl acetate, 2-methyl tetrahydrofuran,isopropyl acetate (IPAc), n-hexane, ethyl acetate (EtOAc), n-heptane,water, an aqueous solvent or supercritical CO₂.

According to another embodiment, the API solution is of a desiredconcentration. According to some such embodiments, the desiredconcentration is of a therapeutically effective amount.

According to another embodiment the therapeutically effective amount is10⁻⁶ weight % to 40 weight % of API in the solvent. According to anotherembodiment the therapeutically effective amount is 10⁻⁶ weight % to 35weight % of API in the solvent. According to another embodiment thetherapeutically effective amount is 10⁻⁶ weight % to 30 weight % of APIin the solvent. According to another embodiment the therapeuticallyeffective amount is 10⁻⁶ weight % to 25 weight % of API in the solvent.According to another embodiment the therapeutically effective amount is10⁻⁶ weight % to 20 weight % of API in the solvent. According to anotherembodiment the therapeutically effective amount is 10⁻⁶ weight % to 15weight % of API in the solvent. According to another embodiment thetherapeutically effective amount is 10⁻⁶ weight % to 10 weight % of APIin the solvent. According to another embodiment the therapeuticallyeffective amount is 10⁻⁶ weight % to 5 weight % of API in the solvent.According to another embodiment the therapeutically effective amount is10⁻⁶ weight % to 1 weight % of API in the solvent.

According to another embodiment the therapeutically effective amount is10⁻⁵ weight % to 40 weight % of API in the solvent. According to anotherembodiment the therapeutically effective amount is 10⁻⁵ weight % to 35weight % of API in the solvent. According to another embodiment thetherapeutically effective amount is 10⁻⁵ weight % to 30 weight % of APIin the solvent. According to another embodiment the therapeuticallyeffective amount is 10⁻⁵ weight % to 25 weight % of API in the solvent.According to another embodiment the therapeutically effective amount is10⁻⁵ weight % to 20 weight % of API in the solvent. According to anotherembodiment the therapeutically effective amount is 10⁻⁵ weight % to 15weight % of API in the solvent. According to another embodiment thetherapeutically effective amount is 10⁻⁵ weight % to 10 weight % of APIin the solvent. According to another embodiment the therapeuticallyeffective amount is 10⁻⁵ weight % to 5 weight % of API in the solvent.According to another embodiment the therapeutically effective amount is10⁻⁵ weight % to 1 weight % of API in the solvent.

According to another embodiment the therapeutically effective amount is10⁻⁴ weight % to 40 weight % of API in the solvent. According to anotherembodiment the therapeutically effective amount is 10⁻⁴ weight % to 35weight % of API in the solvent. According to another embodiment thetherapeutically effective amount is 10⁻⁴ weight % to 30 weight % of APIin the solvent. According to another embodiment the therapeuticallyeffective amount is 10⁻⁴ weight % to 25 weight % of API in the solvent.According to another embodiment the therapeutically effective amount is10⁻⁴ weight % to 20 weight % of API in the solvent. According to anotherembodiment the therapeutically effective amount is 10⁻⁴ weight % to 15weight % of API in the solvent. According to another embodiment thetherapeutically effective amount is 10⁻⁴ weight % to 10 weight % of APIin the solvent. According to another embodiment the therapeuticallyeffective amount is 10⁻⁴ weight % to 5 weight % of API in the solvent.According to another embodiment the therapeutically effective amount is10⁻⁴ weight % to 1 weight % of API in the solvent.

According to another embodiment the therapeutically effective amount is10⁻³ weight % to 40 weight % of API in the solvent. According to anotherembodiment the therapeutically effective amount is 10⁻³ weight % to 35weight % of API in the solvent. According to another embodiment thetherapeutically effective amount is 10⁻³ weight % to 30 weight % of APIin the solvent. According to another embodiment the therapeuticallyeffective amount is 10⁻³ weight % to 25 weight % of API in the solvent.According to another embodiment the therapeutically effective amount is10⁻³ weight % to 20 weight % of API in the solvent. According to anotherembodiment the therapeutically effective amount is 10⁻³ weight % to 15weight % of API in the solvent. According to another embodiment thetherapeutically effective amount is 10⁻³ weight % to 10 weight % of APIin the solvent. According to another embodiment the therapeuticallyeffective amount is 10⁻³ weight % to 5 weight % of API in the solvent.According to another embodiment the therapeutically effective amount is10⁻³ weight % to 1 weight % of API in the solvent.

According to another embodiment the therapeutically effective amount is10⁻² weight % to 40 weight % of API in the solvent. According to anotherembodiment the therapeutically effective amount is 10⁻² weight % to 35weight % of API in the solvent. According to another embodiment thetherapeutically effective amount is 10⁻² weight % to 30 weight % of APIin the solvent. According to another embodiment the therapeuticallyeffective amount is 10⁻² weight % to 25 weight % of API in the solvent.According to another embodiment the therapeutically effective amount is10⁻² weight % to 20 weight % of API in the solvent. According to anotherembodiment the therapeutically effective amount is 10⁻² weight % to 15weight % of API in the solvent. According to another embodiment thetherapeutically effective amount is 10⁻² weight % to 10 weight % of APIin the solvent. According to another embodiment the therapeuticallyeffective amount is 10⁻² weight % to 5 weight % of API in the solvent.According to another embodiment the therapeutically effective amount is10⁻² weight % to 1 weight % of API in the solvent.

According to another embodiment the therapeutically effective amount is0.1 weight % to 40 weight % of API in the solvent. According to anotherembodiment the therapeutically effective amount is 0.1 weight % to 35weight % of API in the solvent. According to another embodiment thetherapeutically effective amount is 0.1 weight % to 30 weight % of APIin the solvent. According to another embodiment the therapeuticallyeffective amount is 0.1 weight % to 25 weight % of API in the solvent.According to another embodiment the therapeutically effective amount is0.1 weight % to 20 weight % of API in the solvent. According to anotherembodiment the therapeutically effective amount is 0.1 weight % to 15weight % of API in the solvent. According to another embodiment thetherapeutically effective amount is 0.1 weight % to 10 weight % of APIin the solvent. According to another embodiment the therapeuticallyeffective amount is 0.1 weight % to 1 weight % of API in the solvent.

According to another embodiment the therapeutically effective amount is1 weight % to 40 weight % of API in the solvent. According to anotherembodiment the therapeutically effective amount is 1 weight % to 35weight % of API in the solvent. According to another embodiment thetherapeutically effective amount is 1 weight % to 30 weight % of API inthe solvent. According to another embodiment the therapeuticallyeffective amount is 1 weight % to 25 weight % of API in the solvent.According to another embodiment the therapeutically effective amount is1 weight % to 20 weight % of API in the solvent. According to anotherembodiment the therapeutically effective amount is 1 weight % to 15weight % of API in the solvent. According to another embodiment thetherapeutically effective amount is 1 weight % to 10 weight % of API inthe solvent. According to another embodiment the therapeuticallyeffective amount is 1 weight % to 5 weight % of API in the solvent.

According to another embodiment the therapeutically effective amount is5 weight % to 10 weight % of API in the solvent. According to anotherembodiment the therapeutically effective amount is 10 weight % to 15weight % of API in the solvent. According to another embodiment thetherapeutically effective amount is 15 weight % to 20 weight % of API inthe solvent. According to another embodiment the therapeuticallyeffective amount is 20 weight % to 25 weight % of API in the solvent.According to another embodiment the therapeutically effective amount is25 weight % to 30 weight % of API in the solvent. According to anotherembodiment the therapeutically effective amount is 30 weight % to 35weight % of API in the solvent. According to another embodiment thetherapeutically effective amount is 35 weight % to 40 weight % of API inthe solvent.

According to another embodiment, the solvent provides good wetability

According to another embodiment, the solvent is not detrimental to theAPI.

According to another embodiment, the solvent has at least one of thefollowing properties: ability to dissolve the API in appropriateconcentrations, low surface tension on carrier surfaces, high vaporpressure, low toxicity, and low or null explosivity, or combinationsthereof.

Porous Carrier

According to another embodiment, the porous carrier is of a highporosity. According to some such embodiments, the porous carrier has ahigh specific surface area. According to another embodiment the porosityof the carrier ranges from 20% to 80% pores by volume. According toanother embodiment the porosity of the carrier ranges from 20% to 75%pores by volume. According to another embodiment the porosity of thecarrier ranges from 20% to 70% pores by volume. According to anotherembodiment the porosity of the carrier ranges from 20% to 65% pores byvolume. According to another embodiment the porosity of the carrierranges from 20% to 60% pores by volume. According to another embodimentthe porosity of the carrier ranges from 20% to 55% pores by volume.According to another embodiment the porosity of the carrier ranges from20% to 50% pores by volume. According to another embodiment the porosityof the carrier ranges from 20% to 45% pores by volume. According toanother embodiment the porosity of the carrier ranges from 20% to 40%pores by volume. According to another embodiment the porosity of thecarrier ranges from 20% to 35% pores by volume. According to anotherembodiment the porosity of the carrier ranges from 20% to 30% pores byvolume. According to another embodiment the porosity of the carrierranges from 20% to 25% pores by volume. According to another embodimentthe porosity of the carrier ranges from 25% to 30% pores by volume.According to another embodiment the porosity of the carrier ranges from30% to 35% pores by volume. According to another embodiment the porosityof the carrier ranges from 35% to 40% pores by volume. According toanother embodiment the porosity of the carrier ranges from 40% to 45%pores by volume. According to another embodiment the porosity of thecarrier ranges from 45% to 50% pores by volume. According to anotherembodiment the porosity of the carrier ranges from 50% to 55% pores byvolume. According to another embodiment the porosity of the carrierranges from 55% to 60% pores by volume. According to another embodimentthe porosity of the carrier ranges from 60% to 65% pores by volume.According to another embodiment the porosity of the carrier ranges from65% to 70% pores by volume. According to another embodiment the porosityof the carrier ranges from 70% to 75% pores by volume. According toanother embodiment the porosity of the carrier ranges from 75% to 80%pores by volume.

According to another embodiment, step (b) provides good flowability.According to another embodiment, step (b) provides tight particle sizedistribution (PSD) of the carrier.

According to some embodiments, the carrier is a pharmaceutical carrier.According to some embodiments, the carrier is CaHPO₄. According to someembodiments, the pharmaceutical carrier is anhydrous CaHPO₄-Emcompress®.

Contacting the API Solution

According to another embodiment, contacting step (b) comprises spraying.According to another embodiment, the spray rate is adjustable. Accordingto another embodiment, the spray rate is a controlled spray rate.According to another embodiment, the spray rate allows for scale-up.

According to another embodiment, spraying is stopped when the desiredAPI content has been achieved.

According to some embodiments, the API impregnated porous carrier is ablend. According to some embodiments, the blend comprises at least oneAPI and at least one porous carrier.

According to another embodiment, the blend comprising the API and porouscarrier is dried. According to some such embodiments, the blend is drieduntil a suitable residual solvent content has been reached. The residualsolvent content is the amount of solvent that remains in the carrierafter drying. Depending on the choice of solvent and its toxicity theresidual solvent content must be below specified limits regulated by theFDA.

According to another embodiment, the contacting temperature is of atemperature appropriate for the solvent. According to another embodimentthe solvent is methanol and the contacting temperature is 25° C. to 55°C. According to another embodiment the solvent is methanol and thecontacting temperature is 25° C. to 50° C. According to anotherembodiment the solvent is methanol and the contacting temperature is 25°C. to 45° C. According to another embodiment the solvent is methanol andthe contacting temperature is 25° C. to 40° C. According to anotherembodiment the solvent is methanol and the contacting temperature is 25°C. to 35° C. According to another embodiment the solvent is methanol andthe contacting temperature is 25° C. to 30° C. According to anotherembodiment the solvent is methanol and the contacting temperature is 30°C. to 35° C. According to another embodiment the solvent is methanol andthe contacting temperature is 35° C. to 40° C. According to anotherembodiment the solvent is methanol and the contacting temperature is 40°C. to 45° C. According to another embodiment the solvent is methanol andthe contacting temperature is 45° C. to 50° C. According to anotherembodiment the solvent is methanol and the contacting temperature is 50°C. to 55° C.

According to another embodiment, the atomization pressure is acontrolled atomization pressure. According to some such embodiments, theatomization pressure is an adjustable atomization pressure.

According to some embodiments, the contactor is a fluidized bed.According to some embodiments, the contactor is an agitated vessel.According to some embodiments, the contactor is a tumbler. According tosome embodiments, the contactor is a stirred vessel. According to someembodiments, the contactor is a tray oven.

According to another embodiment, the porous carrier is impregnated in acontactor, wherein the contactor is a fluidized bed. According toanother embodiment, the porous carrier is impregnated in a contactor,wherein the contactor is a stirred vessel. According to anotherembodiment, the porous carrier is impregnated in a contactor, whereinthe contactor is a tumbler.

Drying the API Impregnated Porous Carrier

According to another embodiment, the API impregnated porous carrier isdried in a contactor. According to some embodiments, the API impregnatedporous carrier is dried in the contactor of step (b). According toanother embodiment, the API impregnated porous carrier is dried in acontactor, wherein the contactor is an agitated vessel. According toanother embodiment, the API impregnated porous carrier is dried in acontactor, wherein the contactor is a tumbler. According to anotherembodiment, the API impregnated porous carrier is dried in a contactor,wherein the contactor is a tray oven.

According to another embodiment, the API impregnated porous carrier isdried in parallel with contacting step (b). According to anotherembodiment, the API impregnated porous carrier is dried after contactingstep (b).

Milling

According to another embodiment, the API impregnated porous carrier(“impregnated carrier”) is milled to improve blend uniformity. Accordingto one embodiment, the particles are milled to obtain particles with aD₉₀ of less than 200 microns. According to another embodiment, theparticles are milled to obtain particles with a D₉₀ of less than 150microns. According to another embodiment, the particles are milled toobtain particles with a D₉₀ of less than 100 microns. According toanother embodiment, the particles are milled to obtain particles with aD₉₀ of less than 50 microns. According to another embodiment, theparticles are milled to obtain particles with a D₉₀ of less than 10microns. According to another embodiment, the particles are milled toobtain particles with a D₉₀ of less than 1 microns.

According to another embodiment, the milling is gentle milling.

According to another embodiment, the blend comprises from about 10% APIw/w/ to about 0.1% API w/w.

Additional Embodiments

According to the described invention, additional embodiments include,but are not limited to, a method, based on fluid bed impregnation, fordistributing one or more active substances across the volume of apreformed porous carrier.

According to another embodiment, the described invention provides amethod, based on fluid bed impregnation, for achieving a substantiallyuniform distribution of one or more active substances across the volumeof a preformed porous carrier.

The term “substantially uniform distribution of one or more activesubstances” as used herein refers to an amount of one or more activesubstances, such that any single active substance content variability ina finished drug product has a relative standard deviation (RSD) of lessthan 3%. According to another embodiment, the single active substancecontent variability in a finished drug product has a relative standarddeviation (RSD) of less than 2.5%. According to another embodiment, thesingle active substance content variability in a finished drug producthas a relative standard deviation (RSD) of less than 2%. According toanother embodiment, the single active substance content variability in afinished drug product has a relative standard deviation (RSD) of lessthan 1.5%. According to another embodiment, the single active substancecontent variability in a finished drug product has a relative standarddeviation (RSD) of less than 1%. According to another embodiment, thesingle active substance content variability in a finished drug producthas a relative standard deviation (RSD) of less than 0.5%. According toanother embodiment, the single active substance content variability in afinished drug product has a relative standard deviation (RSD) of lessthan 0.1%.

According to another embodiment, the described invention provides amethod, based on fluid bed impregnation, for achieving substantiallyuniform distribution of one or more active substances across the volumeof a preformed porous carrier, followed by a additional powderprocessing steps, to be used for making substantially uniformpharmaceutical products containing one of more active substances.

According to another embodiment, the described invention provides amethod, based on fluid bed impregnation, for achieving substantiallyuniform distribution of one or more active substances across the volumeof a preformed porous carrier, followed by a direct compression step, tobe used for making substantially uniform pharmaceutical tabletscontaining one of more active substances.

The tablet, the most frequently prescribed commercial dosage form, isstable, elegant, and effective. It provides the patient with aconvenient product for handling, identification, and administration.Tablets can be prepared using pellet presses or tableting machines.Non-limiting examples of tablets include, but are not limited to,sublingual molded tablets, buccal molded tablets, sintered tablets,compressed tablets, chewable tablets, soluble effervescent tablets, andimplants or pellets.

According to another embodiment, the described invention provides amethod, based on fluid bed impregnation, for achieving substantiallyuniform distribution of one or more active substances across the volumeof a preformed porous carrier, followed by a capsule filling step, to beused for making substantially uniform pharmaceutical capsules containingone of more active substances.

Capsules are solid dosage forms in which the drug is enclosed withineither a hard or soft soluble container or shell. Capsules are generallyof the hard gelatin or soft gelatin type. Hard gelatin capsules can beprepared to release the drug rapidly or over a predetermined time,whereas soft gelatin capsules provide standard release. Hard gelatincapsules consist of two parts: the base and body, which is longer andhas a lesser diameter. This dosage form is intended to be swallowedwhole.

According to another embodiment, the described invention provides amethod, based on fluid bed impregnation, for achieving substantiallyuniform distribution of one or more active substances across the volumeof a preformed porous carrier, followed by an inhaler filling step, tobe used for making substantially uniform pharmaceutical inhalerscontaining one of more active substances.

Inhalation is a method of drug delivery where a dose of a drugincorporated in a properly designed dosage form is introduced throughthe mouth or nose of a patient. The drug is then caught up in the flowof air and carried into the deep recesses of the pulmonary environment,i.e., into the respiratory bronchioles and the alveolar region. Drugscan take the form of a vapor, a very fine powder, or solution in theform of an aerosol. A wide range of dosage forms and methods ofadministering drugs by inhalation is available including, but notlimited to, aerosols, inhalations, insufflations, metered-dose inhalers(MDIs), nebulizers, and vaporizers Inhalants are drugs that can becarried by an air current into the nasal passage where the drugsgenerally exert their effect. The device or the container from which theinhalant is generally administered is called an inhaler.

According to another embodiment, the described invention provides amethod, based on fluid bed impregnation, for achieving substantiallyuniform distribution of one or more active substances across the volumeof a preformed porous carrier, followed by a blister filling step, to beused for making substantially uniform pharmaceutical inhalation productscontaining one of more active substances.

Blister packs, which are commonly used as unit-dose packaging forpharmaceutical powders, tablets, capsules or lozenges, can providebarrier protection for shelf life requirements, and a degree of tamperresistance. Blister packs are created by means of form-fill-seal processwherein the blister packs are created from rolls of flat sheet or film,filled with the pharmaceutical product and closed (sealed) on the sameequipment called blisterline.

According to another embodiment, the described invention provides amethod, based on fluid bed impregnation, for achieving substantiallyuniform distribution of one or more active substances across the volumeof a preformed porous carrier, followed by a vial filling step, to beused for making vials containing substantially uniform powder blends forpharmaceutical applications containing one of more active substances.

According to another embodiment, the described invention provides amethod, based on fluid bed impregnation, for achieving substantiallyuniform distribution of one or more active substances across the volumeof a preformed porous carrier, followed by a milling step and additionalpowder processing steps, to be used for making substantially uniformpharmaceutical products containing one of more active substances.

According to another embodiment, the described invention provides amethod, based on fluid bed impregnation, for achieving substantiallyuniform distribution of one or more active substances across the volumeof a preformed porous carrier, followed by a milling step and additionalpowder processing steps, to be used for making substantially uniformpharmaceutical products containing one of more active substances,followed by a direct compression step, to be used for substantiallyuniform making pharmaceutical tablets containing one of more activesubstances.

According to another embodiment, the described invention provides amethod, based on fluid bed impregnation, for achieving substantiallyuniform distribution of one or more active substances across the volumeof a preformed porous carrier, followed by a milling step and additionalpowder processing steps, to be used for making substantially uniformpharmaceutical products containing one of more active substances,followed by a capsule filling step, to be used for making substantiallyuniform pharmaceutical capsules containing one of more activesubstances.

According to another embodiment, the described invention provides amethod, based on fluid bed impregnation, for achieving substantiallyuniform distribution of one or more active substances across the volumeof a preformed porous carrier, followed by a milling step and additionalpowder processing steps, to be used for making substantially uniformpharmaceutical products containing one of more active substances,followed by an inhaler filling step, to be used for making substantiallyuniform pharmaceutical inhalers containing one of more activesubstances.

According to another embodiment, the described invention provides amethod, based on fluid bed impregnation, for achieving substantiallyuniform distribution of one or more active substances across the volumeof a preformed porous carrier, followed by a milling step and additionalpowder processing steps, to be used for making substantially uniformpharmaceutical products containing one of more active substances,followed by a blister filling step, to be used for making substantiallyuniform pharmaceutical inhalation products containing one of more activesubstances.

According to another embodiment, the described invention provides amethod, based on fluid bed impregnation, for achieving substantiallyuniform distribution of one or more active substances across the volumeof a preformed porous carrier, followed by a milling step and additionalpowder processing steps, to be used for making substantially uniformpharmaceutical products containing one of more active substances,followed by a vial filling step, to be used for making vials containingsubstantially uniform powder blends for pharmaceutical applicationscontaining one of more active substances.

According to another embodiment, the described invention provides amethod, based on fluid bed impregnation, for achieving substantiallyuniform distribution of one or more active substances across the volumeof a preformed porous carrier, followed by a lubrication step andadditional powder processing steps, to be used for making substantiallyuniform pharmaceutical products containing one of more activesubstances.

According to another embodiment, the described invention provides amethod, based on fluid bed impregnation, for achieving substantiallyuniform distribution of one or more active substances across the volumeof a preformed porous carrier, followed by a lubrication step andadditional powder processing steps, to be used for making substantiallyuniform pharmaceutical products containing one of more activesubstances, followed by a direct compression step, to be used for makingsubstantially uniform pharmaceutical tablets containing one of moreactive substances.

According to another embodiment, the described invention provides amethod, based on fluid bed impregnation, for achieving substantiallyuniform distribution of one or more active substances across the volumeof a preformed porous carrier, followed by a lubrication step andadditional powder processing steps, to be used for making substantiallyuniform pharmaceutical products containing one of more activesubstances, followed by a capsule filling step, to be used for makingsubstantially uniform pharmaceutical capsules containing one of moreactive substances.

According to another embodiment, the described invention provides amethod, based on fluid bed impregnation, for achieving substantiallyuniform distribution of one or more active substances across the volumeof a preformed porous carrier, followed by a lubrication step andadditional powder processing steps, to be used for making substantiallyuniform pharmaceutical products containing one of more activesubstances, followed by an inhaler filling step, to be used for makingsubstantially uniform pharmaceutical inhalers containing one of moreactive substances.

According to another embodiment, the described invention provides amethod, based on fluid bed impregnation, for achieving substantiallyuniform distribution of one or more active substances across the volumeof a preformed porous carrier, followed by a lubrication step andadditional powder processing steps, to be used for making substantiallyuniform pharmaceutical products containing one of more activesubstances, followed by a blister filling step, to be used for makingsubstantially uniform pharmaceutical inhalation products containing oneof more active substances.

According to another embodiment, the described invention provides amethod, based on fluid bed impregnation, for achieving substantiallyuniform distribution of one or more active substances across the volumeof a preformed porous carrier, followed by a lubrication step andadditional powder processing steps, to be used for making substantiallyuniform pharmaceutical products containing one of more activesubstances, followed by a vial filling step, to be used for making vialscontaining substantially uniform powder blends for pharmaceuticalapplications containing one of more active substances.

According to another embodiment, the described invention provides amethod, based on fluid bed impregnation, for achieving substantiallyuniform distribution of one or more active substances across the volumeof a preformed porous carrier, followed by a milling and a lubricationstep, in either order, and additional powder processing steps, to beused for making substantially uniform pharmaceutical products containingone of more active substances.

According to another embodiment, the described invention provides amethod, based on fluid bed impregnation, for achieving substantiallyuniform distribution of one or more active substances across the volumeof a preformed porous carrier, followed by a milling and a lubricationstep, in either order, and additional powder processing steps, to beused for making substantially uniform pharmaceutical products containingone of more active substances, followed by a direct compression step, tobe used for making substantially uniform pharmaceutical tabletscontaining one of more active substances.

According to another embodiment, the described invention provides amethod, based on fluid bed impregnation, for achieving substantiallyuniform distribution of one or more active substances across the volumeof a preformed porous carrier, followed by a milling and a lubricationstep, in either order, and additional powder processing steps, to beused for making substantially uniform pharmaceutical products containingone of more active substances, followed by a capsule filling step, to beused for making substantially uniform pharmaceutical capsules containingone of more active substances.

According to another embodiment, the described invention provides amethod, based on fluid bed impregnation, for achieving substantiallyuniform distribution of one or more active substances across the volumeof a preformed porous carrier, followed by a milling and a lubricationstep, in either order, and additional powder processing steps, to beused for making substantially uniform pharmaceutical products containingone of more active substances, followed by an inhaler filling step, tobe used for making substantially uniform pharmaceutical inhalerscontaining one of more active substances.

According to another embodiment, the described invention provides amethod, based on fluid bed impregnation, for achieving substantiallyuniform distribution of one or more active substances across the volumeof a preformed porous carrier, followed by a milling and a lubricationstep, in either order, and additional powder processing steps, to beused for making substantially uniform pharmaceutical products containingone of more active substances, followed by a blister filling step, to beused for making substantially uniform pharmaceutical inhalation productscontaining one of more active substances.

According to another embodiment, the described invention provides amethod, based on fluid bed impregnation, for achieving substantiallyuniform distribution of one or more active substances across the volumeof a preformed porous carrier, followed by a milling and a lubricationstep, in either order, and additional powder processing steps, to beused for making substantially uniform pharmaceutical products containingone of more active substances, followed by a vial filling step, to beused for making vials containing substantially uniform powder blends forpharmaceutical applications containing one of more active substances.

According to another embodiment, the described invention provides amethod, based on fluid bed impregnation, for achieving substantiallyuniform distribution of one or more active substances across the volumeof a preformed porous carrier, followed by a additional powderprocessing steps, to be used for making enhanced bioavailabilitypharmaceutical products containing one of more active substances.

According to another embodiment, the described invention provides amethod, based on fluid bed impregnation, for achieving substantiallyuniform distribution of one or more active substances across the volumeof a preformed porous carrier, followed by a direct compression step, tobe used for making enhanced bioavailability pharmaceutical tabletscontaining one of more active substances.

According to another embodiment, the described invention provides amethod, based on fluid bed impregnation, for achieving substantiallyuniform distribution of one or more active substances across the volumeof a preformed porous carrier, followed by a capsule filling step, to beused for making enhanced bioavailability pharmaceutical capsulescontaining one of more active substances.

According to another embodiment, the described invention provides amethod, based on fluid bed impregnation, for achieving substantiallyuniform distribution of one or more active substances across the volumeof a preformed porous carrier, followed by an inhaler filling step, tobe used for making enhanced bioavailability pharmaceutical inhalerscontaining one of more active substances.

According to another embodiment, the described invention provides amethod, based on fluid bed impregnation, for achieving substantiallyuniform distribution of one or more active substances across the volumeof a preformed porous carrier, followed by a blister filling step, to beused for making enhanced bioavailability pharmaceutical inhalationproducts containing one of more active substances.

According to another embodiment, the described invention provides amethod, based on fluid bed impregnation, for achieving substantiallyuniform distribution of one or more active substances across the volumeof a preformed porous carrier, followed by a vial filling step, to beused for making vials containing enhanced bioavailability powder blendsfor pharmaceutical applications containing one of more activesubstances.

According to another embodiment, the described invention provides amethod, based on fluid bed impregnation, for achieving substantiallyuniform distribution of one or more active substances across the volumeof a preformed porous carrier, followed by a milling step and additionalpowder processing steps, to be used for making substantially uniformpharmaceutical products containing one of more active substances,followed by a direct compression step, to be used for enhancedbioavailability making pharmaceutical tablets containing one of moreactive substances.

According to another embodiment, the described invention provides amethod, based on fluid bed impregnation, for achieving substantiallyuniform distribution of one or more active substances across the volumeof a preformed porous carrier, followed by a milling step and additionalpowder processing steps, to be used for making substantially uniformpharmaceutical products containing one of more active substances,followed by a capsule filling step, to be used for making enhancedbioavailability pharmaceutical capsules containing one of more activesubstances.

According to another embodiment, the described invention provides amethod, based on fluid bed impregnation, for achieving substantiallyuniform distribution of one or more active substances across the volumeof a preformed porous carrier, followed by a milling step and additionalpowder processing steps, to be used for making substantially uniformpharmaceutical products containing one of more active substances,followed by an inhaler filling step, to be used for making enhancedbioavailability pharmaceutical inhalers containing one of more activesubstances.

According to another embodiment, the described invention provides amethod, based on fluid bed impregnation, for achieving substantiallyuniform distribution of one or more active substances across the volumeof a preformed porous carrier, followed by a milling step and additionalpowder processing steps, to be used for making substantially uniformpharmaceutical products containing one of more active substances,followed by a blister filling step, to be used for making enhancedbioavailability pharmaceutical inhalation products containing one ofmore active substances.

According to another embodiment, the described invention provides amethod, based on fluid bed impregnation, for achieving substantiallyuniform distribution of one or more active substances across the volumeof a preformed porous carrier, followed by a milling step and additionalpowder processing steps, to be used for making substantially uniformpharmaceutical products containing one of more active substances,followed by a vial filling step, to be used for making vials containingenhanced bioavailability powder blends for pharmaceutical applicationscontaining one of more active substances.

According to another embodiment, the described invention provides amethod, based on fluid bed impregnation, for achieving substantiallyuniform distribution of one or more active substances across the volumeof a preformed porous carrier, followed by a lubrication step andadditional powder processing steps, to be used for making substantiallyuniform pharmaceutical products containing one of more activesubstances, followed by a direct compression step, to be used for makingenhanced bioavailability pharmaceutical tablets containing one of moreactive substances.

According to another embodiment, the described invention provides amethod, based on fluid bed impregnation, for achieving substantiallyuniform distribution of one or more active substances across the volumeof a preformed porous carrier, followed by a lubrication step andadditional powder processing steps, to be used for making substantiallyuniform pharmaceutical products containing one of more activesubstances, followed by a capsule filling step, to be used for makingenhanced bioavailability pharmaceutical capsules containing one of moreactive substances.

According to another embodiment, the described invention provides amethod, based on fluid bed impregnation, for achieving substantiallyuniform distribution of one or more active substances across the volumeof a preformed porous carrier, followed by a lubrication step andadditional powder processing steps, to be used for making substantiallyuniform pharmaceutical products containing one of more activesubstances, followed by an inhaler filling step, to be used for makingenhanced bioavailability pharmaceutical inhalers containing one of moreactive substances.

According to another embodiment, the described invention provides amethod, based on fluid bed impregnation, for achieving substantiallyuniform distribution of one or more active substances across the volumeof a preformed porous carrier, followed by a lubrication step andadditional powder processing steps, to be used for making substantiallyuniform pharmaceutical products containing one of more activesubstances, followed by a blister filling step, to be used for makingenhanced bioavailability pharmaceutical inhalation products containingone of more active substances.

According to another embodiment, the described invention provides amethod, based on fluid bed impregnation, for achieving substantiallyuniform distribution of one or more active substances across the volumeof a preformed porous carrier, followed by a lubrication step andadditional powder processing steps, to be used for making substantiallyuniform pharmaceutical products containing one of more activesubstances, followed by a vial filling step, to be used for making vialscontaining enhanced bioavailability powder blends for pharmaceuticalapplications containing one of more active substances.

According to another embodiment, the described invention provides amethod, based on fluid bed impregnation, for achieving substantiallyuniform distribution of one or more active substances across the volumeof a preformed porous carrier, followed by a milling and a lubricationstep, in either order, and additional powder processing steps, to beused for making substantially uniform pharmaceutical products containingone of more active substances, followed by a direct compression step, tobe used for making enhanced bioavailability pharmaceutical tabletscontaining one of more active substances.

According to another embodiment, the described invention provides amethod, based on fluid bed impregnation, for achieving substantiallyuniform distribution of one or more active substances across the volumeof a preformed porous carrier, followed by a milling and a lubricationstep, in either order, and additional powder processing steps, to beused for making substantially uniform pharmaceutical products containingone of more active substances, followed by a capsule filling step, to beused for making enhanced bioavailability pharmaceutical capsulescontaining one of more active substances.

According to another embodiment, the described invention provides amethod, based on fluid bed impregnation, for achieving substantiallyuniform distribution of one or more active substances across the volumeof a preformed porous carrier, followed by a milling and a lubricationstep, in either order, and additional powder processing steps, to beused for making substantially uniform pharmaceutical products containingone of more active substances, followed by an inhaler filling step, tobe used for making enhanced bioavailability pharmaceutical inhalerscontaining one of more active substances.

According to another embodiment, the described invention provides amethod, based on fluid bed impregnation, for achieving substantiallyuniform distribution of one or more active substances across the volumeof a preformed porous carrier, followed by a milling and a lubricationstep, in either order, and additional powder processing steps, to beused for making substantially uniform pharmaceutical products containingone of more active substances, followed by a blister filling step, to beused for making enhanced bioavailability pharmaceutical inhalationproducts containing one of more active substances.

According to another embodiment, the described invention provides amethod, based on fluid bed impregnation, for achieving substantiallyuniform distribution of one or more active substances across the volumeof a preformed porous carrier, followed by a milling and a lubricationstep, in either order, and additional powder processing steps, to beused for making substantially uniform pharmaceutical products containingone of more active substances, followed by a vial filling step, to beused for making vials containing enhanced bioavailability powder blendsfor pharmaceutical applications containing one of more activesubstances.

According to another embodiment, the described invention provides amaterial, where one or more active pharmaceutical substances areimpregnated throughout the internal surface of a preformed porouscarrier. According to another embodiment, the active pharmaceuticalsubstance is at least one therapeutic agent.

Where a range of values is provided, it is understood that eachintervening value, to the tenth of the unit of the lower limit unlessthe context clearly dictates otherwise, between the upper and lowerlimit of that range and any other stated or intervening value in thatstated range is encompassed within the invention. The upper and lowerlimits of these smaller ranges which may independently be included inthe smaller ranges is also encompassed within the invention, subject toany specifically excluded limit in the stated range. Where the statedrange includes one or both of the limits, ranges excluding either bothof those included limits are also included in the invention.

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which this invention belongs. Although any method andmaterials similar or equivalent to those described herein can also beused in the practice or testing of the present invention, the preferredmethods and materials are now described. All publications mentionedherein are incorporated herein by reference to disclose and describe themethods and/or materials in connection with which the publications arecited.

It must be noted that as used herein and in the appended claims, thesingular forms “a”, “and”, and “the” include plural references unlessthe context clearly dictates otherwise. All technical and scientificterms used herein have the same meaning

The publications discussed herein are provided solely for theirdisclosure prior to the filing date of the present application. Nothingherein is to be considered as an admission that the present invention isnot entitled to antedate such publication by virtue of prior invention.Further, the dates of publication provided may be different from theactual publication dates which may need to be independently confirmed.

EXAMPLES

The following examples are put forth so as to provide those of ordinaryskill in the art with a complete disclosure and description of how tomake and use the present invention, and are not intended to limit thescope of what the inventors regard as their invention nor are theyintended to represent that the experiments below are all or the onlyexperiments performed. Efforts have been made to ensure accuracy withrespect to numbers used (e.g. amounts, temperature, etc.) but someexperimental errors and deviations should be accounted for. Unlessindicated otherwise, parts are parts by weight, molecular weight isweight average molecular weight, temperature is in degrees Centigrade,and pressure is at or near atmospheric.

Example 1a Impregnation of Porous Carrier with an Active PharmaceuticalIngredient (APAP)

A set of experiments have been conducted successfully using a Glattfluidized bed granulator. The model API used in those experiments wasacetaminophen (APAP) and the porous carrier was anhydrous dibasiccalcium phosphate (CaHPO₄). Among various solvents, methanol was chosendue to its relatively high vapor pressure, low surface tension on thecarrier surface and good solubility of APAP in it. Three subsets ofexperiments were conducted with targeted high, medium and low drugloading. Hard gelatin capsules were then filled with the impregnatedmaterial using a CAP 8 filling machine by Capsugel. Filled capsules weretested for weight variability, content uniformity, and blendhomogeneity. The same impregnated material was afterwards milled andfilled in capsules again to assess the effect that milling has on blenduniformity. A summary of all results is given in Table 1. In some cases,it was observed that the larger particles of porous carrier containedslightly less API than the smaller particles. In such situations, theimpregnated carrier was passed through a pin mill prior to filling itinto capsules in order to erase the correlation between granule size anddrug content and improve uniformity further.

TABLE 1 Blend and Content Uniformity in Capsules Filled with APAPimpregnated CaHPO₄. % APAP Loading Blend Capsule Drug Content (wt API/wtpure Uniformity, Total Weight Uniformity, CaHPO₄) % RSD Variability, %RSD % RSD 8.82% (un-milled) 1.05 2.00 1.73 8.82% (milled) 0.54 1.19 1.651.02% (un-milled) 0.70 1.52 1.18 1.02% (milled) 0.56 1.73 1.91  0.1%(un-milled) 0.99 0.79 1.01  0.1% (milled) 0.42 2.25 2.79

Table 1 shows results obtained from the method for the formulation andmanufacture of solid dosage forms by impregnation in fluidized bed. Thetechnique generates blends with API RSD around 0.5%. Compressed tabletsand/or filled capsules display RSD's<2% for drug content as low as 0.1%and as high as 10%, thus spanning most of the range of interest forpoorly soluble highly potent compounds for oral delivery applications.The results show that the blend uniformity remains essentially unchangedas drug loading is decreased. Further, controlling the spray rate canyield highly uniform blends regardless of the API loading amount.

The ability to obtain low RSD's at low drug content is particularlyimportant because low drug content products typically require lengthydevelopment, usually resulting in complex, expensive, and unreliablemanufacturing methods.

This method has the capability to achieve very uniform blends regardlessof the drug loading. Upon milling, the blend uniformity is furtherincreased, RSD is reduced by almost half. It should be noted thatcapsule filling was performed in a semi-automatic fashion resulting insome inconsistencies in the capsule's total weight variability,affecting in turn the drug content uniformity. All measurements,however, are well below the FDA's requirements.

Example 1b Impregnation of Porous Carrier with an API (APAP)

A porous carrier was impregnated with acetaminophen (APAP) as with themethod described in Example 1a. Table 2 shows the blend and contentuniformity in tablets obtained from the method. In Table 2, theexperiments for 9.91% APAP had particles less than 150 μm eliminatedfrom the CaHPO₄ starting material. This was done in order to see ifeliminating the fine particles of CaHPO₄ improved blend uniformity. Thetablets were produced individually using a PRESSTER.

% APAP Loading Blend Tablet Weight (wt API/wt pure Uniformity,Variability, % Drug Content CaHPO₄) % RSD RSD Uniformity, % RSD 11.69%(un-milled) 1.92 1.07 2.57 11.69% (milled) 0.28 1.75 1.79  9.91%(un-milled) 2.02 1.35 3.17  9.91% (milled) 0.46 1.84 1.71  8.82%(un-milled) 0.67 0.69 1.24

The fluid bed (FB) method yields substantially uniform blends withoutany additives. The results show that milling significantly improvesblend uniformity. FIG. 2A shows photomicrographs of the particularpharmaceutical excipient used—pure anhydrous CaHPO₄. FIG. 2B showsphotomicrographs of different size fractions of CaHPO₄ impregnated withAPAP. Additional properties and characteristics of the compositions andmethods were analyzed.

FIG. 3A shows comparison of XRD patterns for impregnated CaHPO₄ (11.69%loading), pure CaHPO₄ and pure APAP. FIG. 3B shows comparison of XRDpatterns for various sieved fractions of impregnated CaHPO₄ (8.87%average loading).

FIG. 4A shows a graph of DSC analysis of various sieved fractions ofimpregnated CaHPO₄ (8.87% average loading). The DSC profile alwaysexhibits broadening. Without being limited by theory, this may be due tomolecular dispersions in the small pores. From the DSC analysis there isno evidence for amorphous content. FIG. 4B shows a typical DSC profilefor pure and for amorphous APAP.

The drug loading and weight fraction at different size ranges for pureand impregnated CaHPO₄ also was analyzed (FIG. 5).

The specific surface area (SSA) and pore size distribution for varioussieved fractions of impregnated CaHPO₄ with 8.8% loading (FIG. 6) and1.0% loading (FIG. 7) was analyzed.

The dissolution profiles of capsules of different (%) loadings (1.0% and8.8%) were analyzed (FIGS. 8A and 8B). The percentage of dissolved APAPin FIG. 8B, which shows data points over 100%, can be attributed to thefollowing: (1) small errors in the calibration curve used; (2) smallerror in weighing of the capsules; (3) some moisture content in theblend due to uncontrolled storage conditions.

Particle Size Distribution (PSD) measurements were determined (FIGS. 9Aand 9B).

Compressibility experiments were performed using a PRESSTER MMC (FIG.10). The results show that pure CaHPO₄ and CaHPO₄ impregnated with 1%APAP behave similarly. As the impregnated amount increases, for a givencompression force tablet hardness increases and tablet thicknessdecreases; there is an overall increase in compressibility.

Shear Cell by FT4 was investigated (FIG. 11) as well as electrostaticproperties (impedance) (FIG. 12).

FIG. 13 shows an illustrative representation of the effect of millingupon the blend.

These results show that the method has the capability to achieve veryhigh uniformity blends regardless of the drug loading.

Example 2 Impregnation of Porous Carrier with an API (Ibuprofen)

A porous carrier was impregnated with Ibuprofen as with the methodsdescribed in Example 1. The results of blend uniformity of impregnatedCaHPO₄ with Ibuprofen shown in FIG. 14 indicates that the manufacturingmethod of the described invention is not limited to only acetaminophen(APAP) but can be used for any other drug. The average loading shown inFIG. 14 (as determined by HPLC analysis) is slightly higher than thetarget loading. This is due to the fact that there is some loss ofexcipient (primarily very small fines) during the impregnation run,particularly through the bag filter of the fluidized bed. Suchphenomenon will not be seen on large scale fluidized beds with properlysized filter bags.

FIG. 15 (DSC scans of various size fractions of impregnated CaHPO₄ withIbuprofen) also shows an absence of amorphous content (upward peaks) andbroadening of the melting peaks of Ibuprofen, and shifting to lowermelting points (pure Ibuprofen melts at 77.3° C.). This is due toconfinement-induced melting point depression effect, which is well knownin the art, and indicates that the drug is impregnated in small pores.

FIG. 16 shows a dissolution profile of gelatin capsules filled withCaHPO₄ impregnated with Ibuprofen at 10% loading.

Example 3 Impregnation of Porous Carrier with an API(Indometacin/Indomethacin)

A porous carrier is impregnated with Indometacin (or Indomethacin) aswith the methods described in Example 1.

Example 4 Impregnation of Porous Carrier with an API (Flufenamic Acid)

A porous carrier is impregnated with flufenamic acid as with the methodsdescribed in Example 1.

Example 5 Impregnation of Porous Carrier with an API (Imatinib)

A porous carrier is impregnated with Imatinib with the methods describedin Example 1.

Example 6 Impregnation of Porous Carrier with an API (ErlotinibHydrochloride)

A porous carrier is impregnated with erlotinib hydrochloride as with themethods described in Example 1.

Example 7 Impregnation of Porous Carrier with an API (Vitamin D)

A porous carrier is impregnated with vitamin D as with the methodsdescribed in Example 1.

Example 8 Impregnation of Porous Carrier with an API (Steroid)

A porous carrier is impregnated with a steroid as with the methodsdescribed in Example 1.

Example 9 Impregnation of Porous Carrier with an API (Estrodial)

A porous carrier is impregnated with estrodial as with the methodsdescribed in Example 1.

Example 10 Impregnation of Porous Carrier with an API (TherapeuticAgent)

A porous carrier is impregnated with a therapeutic agent as with themethods described in Example 1.

While the present invention has been described with reference to thespecific embodiments thereof, it should be understood by those skilledin the art that various changes may be made and equivalents may besubstituted without departing from the true spirit and scope of theinvention. In addition, many modifications may be made to adopt aparticular situation, material, composition of matter, process, processstep or steps, to the objective spirit and scope of the presentinvention. All such modifications are intended to be within the scope ofthe claims appended hereto.

We claim:
 1. A method for distributing at least one activepharmaceutical ingredient (API) across a volume of a preformed porouscarrier via impregnation, the method comprising: (a) dissolving at leastone active pharmaceutical ingredient (API) in a solvent to form anactive pharmaceutical ingredient (API) solution; (b) contacting a porouscarrier with the at least one active pharmaceutical ingredient (API) of(a) in a contactor to form an active pharmaceutical ingredient (API)impregnated porous carrier; and (c) drying the at least one activepharmaceutical ingredient (API) impregnated porous carrier.
 2. Themethod according to claim 1, wherein the method provides a substantiallyuniform distribution of one or more APIs across the volume of apreformed porous support such that any single active pharmaceuticalingredient (API) content variability in a finished drug product has arelative standard deviation of less than 3%.
 3. The method according toclaim 1, wherein the contacting step (b) and the drying step (c) takeplace in a fluidized bed.
 4. The method according to claim 1, whereinthe active pharmaceutical ingredient (API) impregnated porous carrier isdried in a contactor during step (b).
 5. The method according to claim1, wherein the contactor comprises an agitated vessel, a tumbler, and atray oven.
 6. The method according to claim 1, wherein contacting step(b) comprises spraying.
 7. The method according to claim 1, wherein theat least one pharmaceutical ingredient comprises acetaminophen,ibuprofen, indometacin/indomethacin, flufenamic acid, Imatinib,flufenamic acid, erlotinib hydrochloride, vitamin D, a steroid,estrodial, or a combination thereof.
 8. The method according to claim 1,wherein the preformed porous carrier is of a high porosity of 20% to 80%pores by volume.
 9. The method according to claim 1, wherein the porouscarrier is a pharmaceutical carrier.
 10. The method according to claim1, wherein the porous carrier is CaHPO₄.
 11. The method according toclaim 1, wherein the porous carrier is anhydrous CaHPO₄.
 12. The methodaccording to claim 1, wherein the active pharmaceutical ingredient (API)impregnated porous carrier is a blend.
 13. The method according to claim1, wherein the porous carrier is impregnated in a contactor comprising afluidized bed, a stirred vessel, and a tumbler.
 14. The method accordingto claim 1, further comprising preparing a final dosage form for makinga substantially uniform pharmaceutical product containing the at leastone active pharmaceutical ingredient (API) impregnated porous carrier,wherein the final dosage form is selected from the group consisting of atablet, a powder, a capsule, a blister pack, an inhaler, and a vial. 15.The method according to claim 14, wherein the final dosage form is asubstantially uniform pharmaceutical tablet containing the at least oneactive pharmaceutical ingredient (API) impregnated porous carrier. 16.The method according to claim 14, wherein the final dosage form is asubstantially uniform pharmaceutical powder containing the at least oneactive pharmaceutical ingredient (API) impregnated porous carrier. 17.The method according to claim 14, wherein the final dosage form is acapsule containing the at least one active pharmaceutical ingredient(API) impregnated porous carrier.
 18. The method according to claim 14,wherein the final dosage form is a blister pack containing the at leastone active pharmaceutical ingredient (API) impregnated porous carrier.19. The method according to claim 14, wherein the final dosage form isan inhaler containing the at least one active pharmaceutical ingredient(API) impregnated porous carrier.
 20. The method according to claim 14,wherein the final dosage form is a vial containing a substantiallyuniform powder blend containing the at least one active pharmaceuticalingredient (API) impregnated porous carrier.
 21. The method according toclaim 1, wherein the method further comprises milling and furtherprocessing the at least one active pharmaceutical ingredient (API)impregnated porous carrier.
 22. The method according to claim 1, whereinthe method further comprises lubricating and further processing the atleast one active pharmaceutical ingredient (API) impregnated porouscarrier.
 23. The method according to claim 1, further comprisingpreparing a final dosage form, wherein the final dosage form is selectedfrom the group consisting of a tablet, a powder, a capsule, a blisterpack, an inhaler, and a vial, and wherein the final dosage form producedhas enhanced bioavailability.
 24. The method according to claim 23,wherein the final dosage form is a substantially uniform pharmaceuticaltablet containing the at least one active pharmaceutical ingredient(API) impregnated porous carrier.
 25. The method according to claim 23,wherein the final dosage form is a substantially uniform pharmaceuticalpowder containing the at least one active pharmaceutical ingredient(API) impregnated porous carrier.
 26. The method according to claim 23,wherein the final dosage form is a capsule containing the at least oneactive pharmaceutical ingredient (API) impregnated porous carrier. 27.The method according to claim 23, wherein the final dosage form is ablister pack containing the at least one active pharmaceuticalingredient (API) impregnated porous carrier.
 28. The method according toclaim 23, wherein the final dosage form is an inhaler containing the atleast one active pharmaceutical ingredient (API) impregnated porouscarrier.
 29. The method according to claim 23, wherein the final dosageform is a vial containing a substantially uniform powder blendcontaining the at least one active pharmaceutical ingredient (API)impregnated porous carrier.
 30. An active pharmaceutical ingredient(API)-impregnated porous carrier, wherein at least one activepharmaceutical ingredient (API) is impregnated throughout an internalsurface of a porous carrier.
 31. The according to claim 30, wherein theat least one active pharmaceutical ingredient (API) comprisesacetaminophen, ibuprofen, indometacin/indomethacin, flufenamic acid,Imatinib, flufenamic acid, erlotinib hydrochloride, vitamin D, asteroid, estrodial, or a combination thereof.
 32. The porous carrieraccording to claim 30, wherein the porous carrier is of a high porosityof 20% to 80% pores by volume.
 33. The porous carrier according to claim30, wherein the porous carrier has a high specific surface area.
 34. Theporous carrier according to claim 30, wherein the porous carrier is apharmaceutical carrier.
 35. The porous carrier according to claim 30,wherein the porous carrier is CaHPO₄.
 36. The method according to claim30, wherein the porous carrier is anhydrous CaHPO₄.